Uptake Index of 123I-metaiodobenzylguanidine Myocardial Scintigraphy for Diagnosing Lewy Body Disease

Objective(s): Iodine-123 metaiodobenzylguanidine (123I-MIBG) myocardial scintigraphy has been used to evaluate cardiac sympathetic denervation in Lewy body disease (LBD), including Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). The heart-to-mediastinum ratio (H/M) in PD and DLB is significantly lower than that in Parkinson’s plus syndromes and Alzheimer’s disease. Although this ratio is useful for distinguishing LBD from non-LBD, it fluctuates depending on the system performance of the gamma cameras. Therefore, a new, simple quantification method using 123I-MIBG uptake analysis is required for clinical study. The purpose of this study was to develop a new uptake index with a simple protocol to determine 123I-MIBG uptake on planar images. Methods: The 123I-MIBG input function was obtained from the input counts of the pulmonary artery (PA), which were assessed by analyzing the PA time-activity curves. The heart region of interest used for determining the H/M was used for calculating the uptake index, which was obtained by dividing the heart count by the input count. Results: Forty-eight patients underwent 123I-MIBG chest angiography and planar imaging, after clinical feature assessment and tracer injection. The H/M and 123I-MIBG uptake index were calculated and correlated with clinical features. Values for LBD were significantly lower than those for non-LBD in all analyses (P<0.001). The overlapping ranges between non-LBD and LBD were 2.15 to 2.49 in the H/M method, and 1.04 to 1.22% in the uptake index method. The diagnostic accuracy of the uptake index (area under the curve (AUC), 0.98; sensitivity, 96%; specificity, 91%; positive predictive value (PPV), 90%; negative predictive value (NPV), 93%; and accuracy, 92%) was approximately equal to that of the H/M (AUC, 0.95; sensitivity, 93%; specificity, 91%; PPV, 90%; NPV, 93%; and accuracy, 92%) for discriminating patients with LBD and non-LBD. Conclusion: A simple uptake index method was developed using 123I-MIBG planar imaging and the input counts determined by analyzing chest radioisotope angiography images of the PA. The diagnostic accuracy of the uptake index was approximately equal to that of the H/M for discriminating patients with LBD and non-LBD.

The heart-to-mediastinum ratio (H/M), determined using planar images, has been used for quantifying cardiac 123 I-MIBG uptake (2,7). The H/M in LBD is significantly lower than that in Parkinson's plus syndromes and LBD from Alzheimer's disease (AD) (5,8). However, this method has limited accuracy because the H/M is obtained from twodimensional image analysis, and is significantly affected by scatter from nearby organs and image acquisition parameters. Furthermore, the H/M fluctuates according to system performance (mainly collimator performance: low-energy, medium energy, low-medium energy, etc.) of the gamma cameras (9,10). As a countermeasure, Nakajima et al. described the results of a large Japanese multicenter initiative (84 institutions), reporting cross-institution phantom calibrations for the measurement of the planar H/M by using standard nuclear cameras and collimators from a variety of vendors in order to obtain a standardized H/M (11,12).
However, collimators with the same designation from different vendors have very different characteristics (13). Additionally, a complex experiment using a special phantom is required for calibrating system performance. Therefore, a new, simple method is required for quantifying cardiac 123 I-MIBG uptake. Chen et al. and van der Veen et al. proposed that more accurate and reliable H/ Ms may be obtained using single photon emission tomography (SPECT) imaging (14,15). The results generated for the H/M are a relative uptake measure, and thus depend on the system performance of the gamma cameras. Previously, a quantification method using a retention index of the tracer in positronemission tomography (PET) has been proposed (16,17). The retention index was calculated using the ratio of arterial-blood counts and myocardial counts obtained using 123 I-MIBG cadmium zinc telluride (CZT) SPECT image analysis (18). A simple and noninvasive image analysis technique without arterial blood sampling will also be useful in the clinical setting. Therefore, a simple, noninvasive quantification method using 123 I-MIBG uptake image analysis is required for routine clinical study.
We recently developed an I-123-N-isopropyl-piodoamphetamine ( 123 I-IMP) microsphere method for quantifying cerebral blood flow by using chest dynamic planar images and brain SPECT (19). In addition, we developed a fully automated input function program by using the area under the curve (AUC) of the pulmonary artery (PA) and the integrated lung washout ratio (20). The AUC determination method for the PA could be applied for determining the input counts of 123 I-MIBG (20). The output counts, as determined using the 123 I-MIBG heart counts, could be analyzed using planar images.
The purpose of this study was to develop a new noninvasive quantification method with a simple protocol to determine 123 I-MIBG uptake on planar images.

Theory
The input count obtained using the integrated counts of the time-activity curve (TAC) on the PA region of interest (ROI) of the chest radioisotope (RI) angiography images is directly proportional to the administration dose (20). Therefore, the uptake index can be noninvasively calculated as follows: where output count (counts/pixel) is the heart count on the planar image.
The heart count (counts/pixel) was obtained by subtracting the background (BG) count (counts/ pixel). The BG count was obtained by setting the ROI on the axillary dissection of the planar image. Figure 1 shows the scheme used for determining the uptake index. The first peak of the TAC was fitted with a gamma function, and the AUC was obtained by integrating the gamma functions. The heart ROI used for the H/M method was used for calculating the uptake index ( Figure 1). Table 1 lists the diseases of the patients who visited Chibana Clinic. Images collected from 48 patients (21 men, 27 women; age range: 56-89 years; mean age: 73.5 years) with clinically suspected LBD who underwent both 123 I-MIBG chest RI angiography and planar imaging at the clinic between December 2013 and April 2014 were used for developing the theory and procedure for this new quantification method (Table 1). Clinical diagnosis was performed by a neurologist according to the neurological testing criteria for PD (21), DLB (22), and AD (23). Magnetic resonance imaging was used to rule out related diseases. None of the patients had cardiac disease, diabetes, and pulmonary disease. The age and sex were not significantly different between the patients in the two groups.

Subjects
The study was approved by the Ethics Committee of Medicine at Chibana Clinic and the Kumamoto University for Human Studies, and written informed consent was obtained from all patients before the study began. All imaging data were handled anonymously, in accordance with the guidelines of the Declaration of Helsinki and the regulation of each institution's ethics board.

Study protocol Chest RI angiography
To determine the input function, 123 I-MIBG chest RI angiography images in the anterior view were obtained for 2 min (1 s/frame, 128×128 matrix, and 3.3 mm/pixel) by using a detector equipped with low-medium-energy, generalpurpose collimators after a bolus injection of 111 MBq of 123 I-MIBG. The TAC of the PA was obtained by placing a circular ROI with a diameter of 3 pixels on the dynamic images of the PA (20).

Planar imaging
To determine the output function, a chest planar image was acquired after dynamic image acquisition for 5 min (256×256 [1.45 zoom factor and 3.3 mm/pixel]), and the H/M and uptake index (%) on the planar image were calculated. The H/M was calculated using the method reported by Okuda et al. (7). The correlation between the H/M and uptake index was analyzed with respect to the observed clinical features.

Statistical analysis
Statistically significant differences according to the patients' sex were determined using Fisher's   Figure 2 shows the linear regression analysis between the H/M and uptake index methods. Both values, obtained by these different techniques, were found to be correlated (r=0.77, P<0.001, n=48).   (Figure 3b). The overlapped ranges between non-LBD and LBD were 2.15 to 2.49 in the H/M method, and 1.04 to 1.22% in the uptake index method. The optimal cutoff values of the H/M and uptake index were 2.30, and 1.12, respectively. Figure 4 and table 2 compare ROC curves and diagnostic accuracy of the H/M and uptake index. The diagnostic accuracy of the uptake index (AUC 0.98, sensitivity 96%, specificity 91%, PPV 90%, NPV 93%, accuracy 92%) was approximately equal to the H/M (AUC 0.95, sensitivity 93%, specificity 91%, PPV 90%, NPV 93%, accuracy 92%) for discrimination of the LBD and non-LBD patients.

Discussion
By analyzing chest RI angiography images, we have established a new uptake index method for 123 I-MIBG heart uptake measurements. The input count was calculated by using the integrated counts of the TAC on the PA ROI, by modifying the simple non-invasive 123 I-IMP quantification based on a microsphere model according to the pharmacokinetics of 123 I-MIBG (19,20). The heart count was determined using the same method as the H/M.  (24). Standardization of the H/M method requires the use of a performance conversion coefficient according to system performance. Therefore, a special experiment will be required for calibrating the system in order to obtain the performance conversion coefficient.
Generally, the heart uptake value is obtained by dividing the heart activity (Bq) by the input activity (Bq). When the planar heart and input counts were obtained by one system, the uptake value is calculated without an experimental countactivity conversion calculation (CC), because the CC is offset. Therefore, the uptake value does not depend on the system performance of the gamma cameras. This is an advantage of the uptake index method.
The results of this study were obtained from patients by using a single gamma camera. Further study is necessary to confirm the feasibility of this  method across multiple facilities. The validity and accuracy would ideally need to be confirmed using planar images in a different patient group.
The input count analysis involves complex techniques. Recently, we developed an automated, simple, and noninvasive 123 I-IMP microsphere input function determination program (auto-SIMS program). This program consisted of two ROI setting programs for the PA and lung regions that used the image phase analysis of a chest RI angiogram (20). An automated uptake index program can be easily developed by modifying the PA ROI setting algorithm of the auto-SIMS program. If this program could be developed, subsequent analysis of the uptake index could be completed with one click in a few seconds, without the need for performing complex analyses. In addition, this automated program will improve the repeatability and reproducibility of this uptake method. When the automated program for the uptake index method is completed, this method could be applied as a useful and stable method in routine clinical studies.
Giorgetti et al. reported a quantification method using 123 I-MIBG SPECT with a CZT camera (18). If the uptake index method using 123 I-MIBG SPECT could be developed by referring to their method, its diagnostic accuracy could be improved, such that its diagnostic accuracy was higher than that of the H/M method.

Conclusion
We developed a simple uptake index method by using 123 I-MIBG planar heart and input counts determined by analyzing chest RI angiography images. The diagnostic accuracy of the uptake index was approximately equal to that of the H/M for discriminating patients with LBD and non-LBD. Further testing is necessary to confirm the feasibility of this method in other facilities.